Our recent data have suggested that PPAR-? expression in lung macrophages plays a critical role in sustaining pulmonary anti-influenza effector T cell responses by modulating the survival of T cells within the respiratory tract. Furthermore, our data have indicated that diminished PPAR-? expression and/or function in macrophages predispose obese hosts to impaired pulmonary T cell immunity and enhanced disease development during influenza infection. In this application, we wish to define the underlying cellular and molecular mechanisms by which PPAR-? expression in macrophages modulates respiratory T cell immunity and disease development during influenza infection in normal and obese hosts. We will also test the ability of drugs targeting PPAR-? and downstream factors, including inducible nitric oxide synthase (iNOS), as potential therapeutic agents to reduce influenza virus infection and complications in normal and obese individuals. Aim 1. To elucidate the mechanisms by which myeloid-PPAR-? expression regulates pulmonary anti-viral immunity during influenza infection. Aim 2: To determine the role of dysregulated PPAR-? expression and/or function in macrophages in enhanced susceptibility to influenza infection in obese hosts. Relevance statement: Influenza virus poses a serious challenge to public health. Influenza infection is particularly dangerous for obese people. During the 2009 H1N1 influenza pandemic, for example, obesity was convincingly identified as an independent risk factor for multiple markers of disease severity including hospitalization, intensive care unit admission, and death. Recent rodent studies have also demonstrated that genetic or diet-induced obesity increases host morbidity and mortality after influenza virus challenge. Currently, the mechanisms associated with the increased susceptibility to influenza virus infection in obese hosts remain largely undefined. The proposed research promises to elucidate underlying cellular and molecular mechanisms of severe influenza virus infection in normal and obese hosts. If successful, the results may open the door for drugs to treat severe influenza-associated diseases in obese individuals. Given the serious threat of an influenza pandemic involving highly pathogenic virus strains such as H5N1 and H7N9 in the context of the worldwide increase in the prevalence of obesity, this work promises to have a significant impact on public health.